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Ayurvedic literature
Ayurvedic literature Review
3.2. Anukta Vyadhi Vichar:-
As mentioned in Charak sutrasthana trishothiyadhya that all diseases cant
labeled with some name. The diseases can be studied as a kupita dosha, specific
causes and their sites. Considering vyadhi prakruti-ashaya i.e. sthana is important for
nidana and chikitsa.
The vyadhi mentioned in samhita with its specific samuthana (causes) which
are responsible for aggravation of doshas. The samuthana leads to ashaya / sthana
(site) in particular for the expression of vyadhi such as amashaya and Pakavashaya.
The vyadhi is having its own akruti (shape) such as Gulma and Arbuda. The labeling
or nomenclature of single disease as Rajayakshma / Shosha is mentioned in samhita.
The Sthula vikara are grossly classifiable in Udara, Mutrakruchha but remaining
asthul vyadhi should be considered as prakrutisamanyam i.e. causes and dosha dushti
according to it. Then it is named as per dominance of doshas and dhatus vata, pitta or
kaphaj or rasa, rakta respectively.
4

The Anukta Vyadhi concept as elaborated in laghanbhrubaniya adhyaya
Sansarg and Sannipat may be of various types of various chikitsa are mentioned
individualy or grouped (sankirnata) respectively. As mentioned in langhanbhrruniya
adhaya though the pattern and types of chikitsa are different grouped into only six
types laghan & bruhan. Thus the method to study the Anukta Vyadhi is to study the
causes, dosha and sthanas respectively.
5

The vatadi dosha sansarg and sannipat are of different types but the doshas
are of only three though the vyadhi is anukta but it can be classified on the
dominance of dosha or doshas involved.
The Anukta Vyadhi is priory swatantra having its own potential after that it
may cause other vyadhi. In that case one disease is cause for other disease.
6



4
Ch. Su. 18/45, Page 108.
5
Ch. Su. 22/43 Page 122
6
Ch. Ni. 8/21-22, Page 228


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Ayurvedic literature
Vyadhi avastha or Anukta Vyadhi can be studied as minute changes in i.e.
vruddhi, kshaya and sthana. As well sharir, Agni, bala and state of kshaya, vruddhi
and sthana are to be studied particularly.
7

Vyadhi and Lakshana Relation:-
The vyadhi is group or individual lakshana evidence. In Anukta vyadhi the
disease in not specifically labeled it is group of lakshana and may be labeled as
lakshana samuchya. Thus the symptom complex is not labeled as a disease as it is
having some disease in past history.
8

In particular disease / vyadhi the - Prakopa, Yoni-uthana, Atma, Adhisthana,
Vedana, Sansthana, Shabda, Sparsha, Roopa, Rasa, Gandha, Upadrava, Vruddhi,
Sthana, Kshaya, Udaraka, Chikitsa are considered. Same with Anukta Vyadhi these
are the highlighting points to assess the symptom complex as it is not labeled with
specific name. The same methodology is implemented to study here to deal with
CKD.
Dushit doshas are main causes for all diseases. All the different kinds of
diseases cannot be devoid of the doshas. Even though, those caused by dushta
dhatus, cannot be without the involvement of the doshas.
9

The physician should never feel shy for not knowing the nomenclature of the
disease, for these there is no rule/ custom/ state that every disease has a name. The
very same dosha, depending upon the nature of the causes circulate to other parts of
the body and produces many diseases hence treatment should be targeted
determining the nature of the disease site and its causes.
10

To study Anukta Vyadhi these methods are illustrated in samhita. Thus to study
aetiopathogenesis of CKD, these pathways are used. Such as dosha prakopa, vruddhi,
Sthana, Lakshana, Samuthana causes are studied.


7
Ch. ni. 8/36, 37, page 229
8
Ch. ni 8/40, page 229
9
A. Hr. Su. 12/32, page197
10
A. Hr. Su. 12/ 64-66, page 206


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Ayurvedic literature
So, considering all above information related to CKD, it suggests dealing with CKD
Ayurveda aspect in the same way. These are the sthana (Vrukka Sharir, Sharir Kriya,
Involved Dosha, Agni, Dhatu etc.) same methodology is followed in the wholesome study.
Particularly Kleda, Mutra, Sweda, Pakawakshaya, Agni & Pachana are important among
them.
Sharir Basti, Vrukka, Gavini, Mutravaha Strotas
As stated in Khudika Garbhavkranti Adhyaya formation of Garbha is due to
Shukra & Artava. Matruja bhava is one of the six bhava of Garbhotpathi. Matruja
Ahara rasa nourishes Garbha eventually ends in the formation of individual.
Twaka, Nabhi, Hridya, Kloma, Yakruta, Pliha, Vrukka, Vasti, Purishadhana,
Amakshaya, Pakawakshaya, Uttar and adharguda, Shudrantra, & Vapa are maturja
organs.
11

Vrukka Matruja Avayava:-
The twak lohit, mamsa, meda, nabhi Hrudya, klom, yakrut, pliha, vrukka,
basti and purishadhana are maturjavayuva.
12

Vrukka and Mahabhuta Relation:-
Pruthavi Vrukka akara
Jala Kleda and Mutra
Tej Tej mahabhuta for blood filtration with formation of mutra
Vayu All functions of vrukka
Akasha Maintains sachidrata porosity.
13

Vrukka and Dhatu: - Vrukka is formed from Rakta and Meda dhatu mainly.
14

Vrukka Mulsthana: - Vrukka is mulsthana for Medavaha Strotas.
15

Vrukka Dosha: - Tridosha with Kapha dominances.

11
Ch. Sh.3/6, page 310
12
Su. Sa. 4/31
13
Ch. Su. 26/11, page 138
14
As. Sa. 5/28
15
Ch. Vi. 5/8, page 251


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Ayurvedic literature
Strotas hetu and dushti lakshana:
Medovaha Strotas: Day sleep, Fatty food and Alcoholic drinks.
Dushti Lakshana: Prameha Purupa.
Mutravaha Strotas: The basic site for mutravaha Strotas is mutrashaya and
vankshana.
Dushti lakshana: Bahumutrata, Alpamutrata, Mutra Avarodha, Buring Urination,
Mutra Gandha, Varna changes.
Purishavaha Strotas: Pakawakshaya and guda
PurishaStrotas Lakshana: Shashoola, Sakashta, Sarakta, Pravartana.
Swedavaha Strotas: Meda and lomakup
Dushti lakshana: Daha, lomaharsha, excess sweating, less sweating dryness of
skin.
16

Dosha & Mutra:-
The tridosha nirmiti in the body is output of digestive process that is pachana.
Here pachana means it is of the Ahara taken by individual for his daily energy
requirement. The daily diet consumption is processed through pachanasanstha. This
is directly related to the basic three avasthapakas respectively forming prakrut kapha,
Pitta & Vata. Further the remaining (Pachit Ahara rasa) part after formation of the
tridoshas is directed / circulated throughout the body. During this process the
particular dhatus take necessary part for their poshana individually.
This is the basic pachana process in digestive system labeled as three
avasthapaka which is not possible without kayagni.
The rest remaing part is already having mala in avyaktarupa where mutra is
also avyakt in jaliya form as it is with the dhatuposhanka ghatak.
\

16
Ch. Vi. 5/8,14-16, page 250,251


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Ayurvedic literature
The same rasa circulating throughout the body nourishes the individual dhatu
with their respective ghatak. Hence this is the sukshma pachana nourishing the
dhatus. The jaliya part again in avyakta form is given back to the circulating rasa.
Here during sukshma pachana meda dhatu is the chief among the sevan
dhatus which contributes on higher side for kleda formation.
Thus sthula pachana is occurred in pachana sanstha level & sukshma pachana
is at dhatu level, simultaneously form the avyakta mutra which at terminal stage is
given vykta mutra form at mutrakshaya level. (Vrukka vasti)
Formation of Urine:-
Saman Vayu facilitate pachana with the help of Kledaka Kapha to reduce the
Kledan karma facilitate Pachaka strava from Amashaya, Pachamanasahya, Yakrut
and Agnyashaya. This helps in formation of Teja, Drava and sukshma Ahara and
separation of mala into Saara & kitta. The ahara rasa absorbed by Grahani and
forwarded towards heart (by rasa dhamanya for further body nourishment).
17

This antrapachan gives rise to dosha formation. The dosha similar guna
ghataka absorbed in rasa and nourishes for dosha. This is the vital function of
Samaan Vayu.
Samaan Vayu Prakupit Vikaras are Gulma, Atisaara and Agnimandya etc.

Mutra Pravartara Excretion urine
18

The apana vayu site is Vrushna, Vrukka, Basti, Gavini, Nabhi, Uru & Guda.
19

When the bladder is completely filled with urine, it is excreted with the
stimulus of Apana Vayu.
Apana Vayu Prakupita Vyadhi:
The apana vayu vitiation leads to Mutragrha, Garbhastrava and Bhagandra.
20



17
Va. Su. 12/8, page 55
18
Va. Su.12
19
Ch. Chi. 28/10, page 616
20
Su. Ni. 1


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Ayurvedic literature
Pitta dosha:
Pitta vruddhi Lakshana This leads to yellow coloration of mutra.
21

Pittakshaya: The functions of pachak pitta is hampered due to which Agnimandya
& Anannabhilasha and the whole body get pale due to kkshaya of pitta.
Yakrut in Mutra Nirmiti:
Amashaya Grahani, Pakawashaya and their respective avasthapaka -Madhur,
Amla & Katu. This ahara rasa formed in avasthapaka basically circulated from
Yakrut to heart. The state of ahara rasa depending upon which type of ahara is taken
is processed by Yakrut. The function of Yakrut is to maintain ahara rasa Atisukshma
& Saarabhut in nature. Remaining portion which is not completely pachit is cleared
by Yakrutastha Agni. The kitta paramanu formed in Yakrut mix with kleda and
excreted as mutra.
22

Rakta Dhatu: Functions of Rakta dhatu are Varna Prasadana, Indriya Prasadana,
Indriya vishaya grahana & timely excretion of mala.
23

Meda dhatu:
The Meda dhatu nirmiti is followed by mamsadhatu with the help of
medadhatuagni. Meda dhatu consists of jal mahabhuta dominant aliment and sneha
dominant aliment. The sira and snayu are updhatu of meda.
24

Vrukka mutra and sweda:
The kapha & meda properties are approximately same in nature. The kleda
portion of kapha partly store in meda dhatus when needed used by sharir. As well if
this kleda becomes excess stored in Vrukka and regulated as mutra & sweda. The
sneha of majjadhatu keeps Twaka Varna in prakrutika condition. It helps in
raktotpatti with Yakrut, Pliha & Sira.


21
Va.Su. 11/7, page 52

22
Doshadhatu malavidgyma page 102.
23
Ch. Su. 24/24
24
Su. Sh.


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Ayurvedic literature
Pachana and Mutra roga:
The Abhojana Ajeerna, Atibhojana, Vishmashna, Asatmya, Guru, Sheet,
Rooksha bhojana leads to disturbances of Agni. The dushitagni is unable to digest
laghuahara too; Disturbed pachana gives shuktatva to ahara forming Aharvisha. The
portion leads to Mutrsanga and Mutravikara.
25

The above mentioned hetus for Agni dushti are responsible for pachan
vikruti. Also the dushti ahara rasa with vyana vayu circulated throughout Sharir.
The vikruti observed in sthana vaigunaya.
26

This leads to rasa dhatu dushti. This dushit rasa dhatu with vyana vayu
circulated throughout body. It is lodged where basic vaigunaya i.e. Khavaigunya is
present.
Krimi Pachana (Lakshane samuchya seen in pt)
The kshira, guda, tila, matsaya (anoop), pistanna, jreerna, puti, klinna,
viruddha ahara, leads to shlemajakirmi. These krimi gives rise lakshanas such as
Murchha, Jrumbha, Aanaha, Agmarda, Chhardi, Karshya and Parushya.
27




25
Ch. Chi. 15/49, page 517
26
Ch. Chi. 15/36, page 516.
27
Ch. Vi. 7/12


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Ayurvedic literature
Mutra and Kleda:-
The pachana of ahara is passed through Avasthapaka.

Kleda and Ahara parinamkarbhava:-
For proper ahara pachana ushma, vayu, kleda, sneha, kala, samyog all these
factors are needed.
28




28
Ch. Su. 6/14, page 332

Ahara
Three Avasthapaka
Saara kitta vibhajana
Ambu Jaliya
Kleda Kleda
Udakavahastrotas ambuvahastrotas kittaportion absorbed by all jaliya dhosha
poshana + Pakvasaya

Circulated throughout sharir with
Vyana Vayu

Vrukka

Mutranirmiti

Flow Chart No. 1 Mutra and Kleda


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Ayurvedic literature
Kleda and Prameha:-
The sharistha kleda is mixed with shleshma and meda. This is driven toward
mutrakshaya. The properties such as shewta, sheet, murt, pichil, snigdha, madhur,
Sandra leads to type of Kaphajmeha.
29

Kleda and Vata rakta: - The dushit kleda and vata results in vata rakta.
30

Kleda & Pitta: The kleda with shonit leads to tanutva of rakta dhatu.
31

The mamsa kleda leads to pittaroga.
32

Kleda Rasa: -
The lavana rasa with dushit kleda gives rise to mutra daha, as Lavana rasa is
basically ushna, tikshna and upa-kledi.
33

Kleda Madya:-
The excess madya sevana leads to Vidahi, Vidagdha and Kleda Vruddhi
causing ksharatva.
Sweda:-
Sweda-Mutra- Upadrava:
The dushti of vata dosha leads to pachana sweda and mutra avarodha. The
dushit vayu with urdhva gamitva causes Strotas avarodha of meda, sweda, mutra and
ambu (uadaka). This gives rise to Chhardi, Hikka, and Shwasa.
34

Sweda and kleda: - The sweda protects the roma as well twak sneha.
35

Swedavaha Strotas Dushti Lakshana:
The dushti lakshana of swedavaha Strotas are twakparushatva, aswedsna, excess
sweda, Paridaha, Lomaharsha.


29
Ch. Chi. 6/51
30
Ch. Chi 29/27, page 629
31
As. Sa. Su. 20/10
32
Ch. Su. 20/14
33
Ch. Su.26/67
34
Ch. Chi. 20/16, page 556
35
As. Su. 19/2


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Ayurvedic literature
Sweda vruddhi Lakshana: - Sweda vruddhi lakshana are kandu & gandha vikruti.
36

Manasaguna Sweda:-
The viharia hetu Vyayama, krodha, sheet followed by ushnas & shoka leads
to sweda dushti.
37

Sweda vrudhi & sweda kshina lakshana:-
Sweda vruddhi leads to kandu and daurgandhya. Sweda kshaya leads to hair
fall, and dry scaly skin.
38

Harita samhita:-
Harita samhita mentioned Arishtas lakshanas of Ashamari, Prameha, and
Pandu vyadhi. The Pandu vyadhi Arishtas are Shopha, Shwas, Pipasa, Shoola. The
Prameha Aristas are excessive stravas and Prameha pitika.
39

Rajnighantu:-
Rajnighantu mentioned mutra dosha Prameha, Mutra Kruchha, Mutra Rodha
is labeled as mutra ashmari.
40

Pakvasaya sharir:-
Pakvasaya is matruja avayva it is a site of vata. The dhamnaya of Pakvasaya
carry Vata, Pitta & Kapha Dosha, Udaka, Mutra, Shuddha Rakta, Shukra, Artava and
Purisha. The dushit dosha in Pakvasaya leads to Kati Shotha.
41

The Pakvasaya is udbhava sthana of hikka. The apana prana vayu leads to
hikka.
Vega: The Vega vidharana of adharaniya vega is one of the dushti cause of
mutravaha Strotas.


36
Va. Su. 11/14
37
Ch. Chi. 15/239
38
Va. Su. 11/22
39
Ha. Sa. 2/4124
40
Ra. Ni.
41
Su. Chi. 23/6



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Ayurvedic literature
Dharaniya: The significance of Dharana to settle, restore for some time is dharana.
It may be the kayic, vachic and manasic.
Adharaniya: There are thirteen adharaniya Vegas are mentioned. Mutra, Mala,
Shukra, Apana, Chhardi, Shvyathu, Udagara, Trishana, Shudha, Jrumbha Ashru, and
Nidra, Shramashwasa.
Mutra Vega vidharana lakshana: Vasti, vinama, mutra krushratva, shirashoola and
vanshana anaha.
Mala Vega vidharana lakshana: Shirashoola, Malavabaddhata, Pindikodweshatan,
Adhamana.
Apana vayu vidharana lakshana: The Vata, Mutra Mala Sanga, Adhamana,
Klama, Udarshoola and Vata Vikara.
Chhardi Vega vidharana: Kandu, Kotha, Aruchi, Vyanga, Shotha, Pandu, Jwara,
Kushta, Hrullasa and Visaarpa
Shvayuthu Vega vidharana lakshana: Manyastambha, Shirashoola, Ardit,
Ardhavabhedaka and Indriyadrubalya.
Udagara Vega vidharana: The Hikka, Kasa, Aruchi, Urogaurava seen.
Jrumbha Vega vidharana: Vinama, Akshepa, Sankocha, Supti, Kampa seen
Shudha Vega vidharana: Karhsya, Daruballya, Vaivaranya, Agagmarda, Aruchi,
Bhrama seen.
Trishana Vega vidharana Lakshana: Kantha and Mukha Shosha, Badhiraya,
Shrama, Angasada, Hrudavedana.
Ashru Vega vidharana: Pratishya, netravikara, hrudvikara as well aruchi, bhrama.
Nidra Vega vidharana: Jrumbha, Aganmarda, Tandra, Shirogaurava and Netra
Gaurava.





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Shramashavasa: Gulma, Hrudroga, Samhoha
Dharaniya Vega:
Manasa Vega: Lobha, Shoka, Krodha, Ahankara, Irsha.
Vachic Vega: Bhashana, lies and all.
Sharirik Vega: Stealing,





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Modern literature Review
3.3. Physiologic Anatomy of the Kidneys:
Kidneys and Urinary tract:-
The two kidneys lie on the posterior wall of the abdomen, outside the
peritoneal cavity (Figure). Each kidney of the adult human weighs about 150 grams
and is about the size of a clenched fist. The medial side of each kidney contains an
indented region called the helium through which pass the renal artery and vein,
lymphatic, nerve supply, and urethra, which carries the final urine from the kidney to
the bladder, where it is stored until emptied. The kidney is surrounded by a tough,
fibrous capsule that protects its delicate inner structures.
If the kidney is bisected from top to bottom, the two major regions that can be
visualized are the outer cortex and the inner region referred to as the medulla. The
medulla is divided into multiple cone-shaped masses of tissue called renal pyramids.
The base of each pyramid originates at the border between the cortex and medulla
and terminates in the papilla, which projects into the space of the renal pelvis, a
funnel-shaped continuation of the upper end of the urethra. The outer border of the
pelvis is divided into open-ended pouches called major calyces that extend
downward and divide into minor calyces, which collect urine from the tubules of
each papilla. The walls of the calyces, pelvis, and urethra contain contractile
elements that propel the urine toward the bladder, where urine is stored until it is
emptied by micturition.
42




42
Text book of Medical Physiology 11
th
edition 308-309.


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Modern literature Review
Functions of kidney:
Renal Blood Supply:-
Blood flow to the two kidneys is normally about 22 per cent of the cardiac
output, or 1100 ml/min. The renal artery enters the kidney through the hilum and
then branches progressively to form the interlobular arteries, arcuate arteries,
interlobular arteries (also called radial arteries) and afferent arterioles, which lead to
the glomerular capillaries, where large amounts of fluid and solutes (except the
plasma proteins) are filtered to begin urine formation (Figure 26 3). The distal ends
of the capillaries of each glomerular coalesce to form the efferent arteriole, which
leads to a second capillary network, tubular capillaries, that surrounds the renal
tubules.
Excretion Of Metabolic Waste Products, Foreign Chemicals, Drugs, And
Hormone Metabolites:-
The kidneys are the primary means for eliminating waste products of
metabolism that are no longer needed by the body. These products include urea
(from the metabolism of amino acids), creatinine (from muscle creatnine), uric acid
(from nucleic acids), end products of hemoglobin breakdown (such as bilirubin), and
metabolites of various hormones. These waste products must be eliminated from the
body as rapidly as they are produced. The kidneys also eliminate most toxins and
other foreign substances that are either produced by the body or ingested, such as
pesticides, drugs, and food additives.
The Nephron is The Functional Unit of The Kidney:-
Each kidney in the human contains about 800,000 to 1 million nephrons, each
capable of forming urine. The kidney cannot regenerate new nephrons. Therefore,
with renal injury, disease, or normal aging, there is a gradual decrease in nephrons
number. After age 40, the number of functioning nephrons usually decreases about
10 per cent every 10 years; thus, at age 80, many people have 40 per cent fewer
functioning nephrons than they did at age 40. This loss is not life threatening because
adaptive changes in the remaining


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Modern literature Review
Nephrons allow them to excrete the proper amounts of water, electrolytes, and waste
products.
Micturition:-
Micturition is the process by which the urinary bladder empties when it
becomes filled. This involves two main steps; first, the bladder fills progressively
until the tension in its walls rises above a threshold level; this elicits the second step,
which is a nervous reflex called the micturition reflex that empties the bladder or, if
this fails, at least causes a conscious desire to urinate. Although the micturition reflex
is an autonomic spinal cord reflex, it can also be inhibited or facilitated by centers in
the cerebral cortex or brain stem.
Facilitation or Inhibition of Micturition by the Brain:-
The micturition reflex is a completely autonomic spinal cord reflex, but it can
be inhibited or facilitated by centers in the brain. These centers include (1) strong
facilitative and inhibitory centers in the brain stem, located mainly in the pons, and
(2) several centers located in the cerebral cortex that are mainly inhibitory but can
become excitatory.
The micturition reflex is the basic cause of micturition, but the higher centers
normally exert final control of micturition as follows:
The higher centers keep the micturition reflex partially inhibited, except
when micturition is desired.
The higher centers can prevent micturition, even if the micturition reflex
occurs, by continual tonic contraction of the external bladder sphincter until a
convenient time presents itself.
When it is time to urinate, the cortical centers can facilitate the sacral
micturation centers to help initiate a micturition reflex and at the same time
inhibit the external urinary sphincter so that urination can occur.





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Modern literature Review
Voluntary urination is usually initiated in the following way: First, a person
voluntarily contracts his or her abdominal muscles, which increases the pressure in
the bladder and allows extra urine to enter the bladder neck and posterior urethra
under pressure, thus stretching their walls. This stimulates the stretch receptors,
which excites the micturition reflex and simultaneously inhibits the external urethral
sphincter. Ordinarily, all the urine will be emptied, with rarely more than 5 to 10
milliliters left in the bladder.
43

Etiology and Epidemiology:-



43
Text book of Medical Physiology 11
th
edition 307-308.
TABLE 2 : Population at Risk for CKD
Age >65
Diabetes type 1 and 2
Family history of renal disease
Autoimmune disease
Systemic infections
Urinary tract infections/ stones
Urinary tract obstructions
Recovery of acute kidney injury
Hypertensives
Drug abusers: Non-steroidal anti inflammatory drugs (NSAIDs), analgesics/
heroin
Neoplasia
Low birth weight
Reduced kidney mass
Low income
Low education
*Perhaps, an appropriate name for this group of patients would be CKD stage
0.


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Modern literature Review
The most frequent cause of CKD is diabetic nephropathy, most often
secondary to type 2 diabetes mellitus. Hypertensive nephropathy is a common cause
of CKD in the elderly, in whom chronic renal ischemia as a result of small and large
vascular disease may be under recognized. Progressive nephrosclerosis from vascular
disease is the renal correlate of the same processes that lead to coronary heart disease
and cerebro vascular disease. The increasing incidence of CKD in the elderly has
been ascribed, in part, to decreased mortality from the cardiac and cerebral
complications of atherosclerotic vascular disease in these individuals, enabling a
greater segment of the population to manifest the renal component of generalized
vascular disease. Nevertheless, it should be appreciated that overwhelmingly the vast
majority of those with early stages of renal disease, especially of vascular origin, will
succumb to the cardiovascular and cerebro vascular consequences of the vascular
disease before they can progress to the most advanced stages of CKD. The early
stage of CKD, manifesting as albuminuria and even a minor decrement in GFR, is
now recognized as a major risk factor for cardiovascular disease.
The striking inter individual variability in the rate of progression to CKD has
an important heritable component, and a number of genetic loci that contribute to the
progression of CKD have been identified. Similarly, it has been noted that women of
reproductive age are relatively protected against progression of many renal diseases,
and sex-specific responses to angiotensin II and its blockade have been identified.
44

Pathophysiology of CKD:-
Chronic Kidney disease is any illness that has existed for > 3 months with
either kidney damage or low GFR. Kidney damage manifests as abnormal gross or
histopathological abnormality or investigation revel urinary abnormality,
biochemical abnormality & imaging abnormality indicating kidney dysfunction.
Pathophysiology of Chronic Kidney Disease:-
The Pathophysiology of CKD involves two broad sets of mechanisms of
damage:

44
API text book of Medicine, 8
th
edition, vol. I, page 733.


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Modern literature Review
(1) Initiating mechanisms specific to the underlying etiology (e.g., immune
complexes and mediators of inflammation in certain types of glomerular
nephritis, or toxin exposure in certain diseases of the renal tubules and
interstitium).
45

Immune mechanism
Inflammation
Toxins
(2) A set of progressive mechanisms, involving hyper filtration and hypertrophy
of the remaining viable nephrons, that are a common consequence following
long-term reduction of renal mass, irrespective of underlying etiology. The
responses to reduction in nephrons number are mediated by vasoactive
hormones, cytokines, and growth factors. Eventually, these short- term
adaptations of hypertrophy and hyper filtration become maladaptive as the
increased pressure and flow predisposes to sclerosis and dropout of the
remaining nephrons. Increased interregnal activity of the rennin- angiotensin
axis appears to contribute both to the initial adaptive hyper filtration and to
the subsequent maladaptive hypertrophy and sclerosis, the latter, in part,
owing to the stimulation of transforming growth factor (TGF- ). This
process explains why a reduction in renal mass from an isolated insult may
lead to a progressive decline in renal function over many years.
46

The Stages of CKD and Identification of At- Risk Populations:-
It is important to identify factors that increase the risk for CKD, even in
individuals with normal GFR.
Risk factors
Hypertension, Diabetes mellitus, autoimmune disease,




45
Harrisons internal medicine 17
th
edition II, 1762.
46
The Text book of Pathology-Harsha mohan chapter 20 The Kidney and Lower urinary Tract.


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Older age, African ancestry, a family history of renal disease, h/o Acute Renal
Failure, presence of proteinuria, abnormal urinary sediment, or structural
abnormalities of the urinary tract.
Etiopathogenesis:-
All chronic nephropathies can lead to CRF. The diseases leading to CRF can
generally be classified into two major groups: those causing glomerular pathology,
and that causing tubulointerstitial pathology. Though this classification is useful to
facilitate study, the disease rarely remains confined to either glomerular or
tubulointerstitial tissue alone. In the final stage of CRF, all parts of the nephrons are
involved.
Diseases causing glomerular pathology:-
A number of glomerular diseases associated with CRF have their
pathogenesis in immune mechanisms (page 685). Glomerular destruction results in
changes in filtration process and leads to development of the nephritic syndrome
characterized by proteinuria, hypoalbuminaemia and edema. The important examples
of chronic glomerular diseases causing CRF are covered under two headings:
primary and systemic.
I. Primary glomerular pathology
II. Systemic glomerular pathology

Diseases causing tubulointerstitial pathology:
Damage to tubulointerstitial tissues results in alterations in reabsorption and
secretion of important constituents leads to excretion of large volumes of dilute
urine. Tubulointerstitial diseases can be categorized according to initiating etiology
into 4 groups: vascular, infections, toxic and obstructive.





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I. Vascular causes: Long-standing primary or essential hypertension produces
characteristic changes in renal arteries and arterioles referred to as
nephrosclerosis. Nephrosclerosis causes progressive renal vascular occlusion
terminating in ischemia and necrosis of renal tissue.
II. Infections causes: A good example of chronic renal infection causing CRF is
chronic pyelonephritis. The chronicity of process results in progressive
damage to increasing number of nephrons leading to CRF.
III. Toxic causes: Some toxic substances induce slow tubular injury, eventually
culminating in CRF. The most common example is intake of high doses of
analgesics such as phenacetin, aspirin and acetaminophen (chronic analgesic
nephritis). Other substances that can cause CRF after prolonged exposure are
lead, cadmium and uranium.
IV. Obstructive causes: Chronic obstruction in the urinary tract leads to
progressive damage to the nephrons due to fluid back-pressure. The examples
of this type of chronic injury are stones, blood clots, tumors, strictures and
enlarged prostate.
Pathophysiology and Biochemistry of Uremia:-
Although serum urea and creatinine concentrations are used to measure the
excretory capacity of the kidneys, accumulation of these two molecules themselves
do not account for the many symptoms and signs that characterize the uremic
syndrome in advanced renal failure. Hundreds of toxins that accumulate in renal
failure have been implicated in the uremic syndrome. These include water-soluble,
hydrophobic, protein-bound, charged, and uncharged compounds. Additional
categories of nitrogenous excretory products include guanido compounds, urates and
Hippocrates, products of nucleic acid metabolism, polyamines, myoinositol, phenols,
benzoates, and in doles. Compounds with a molecular mass between 500 and 1500
Da, the so-called middle molecules, are also retained and contribute to morbidity and
mortality. It is thus evident that the plasma concentrations of urea and creatinine
should be viewed as being readily measured, but incomplete, surrogate markers for




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Modern literature Review
these compounds and monitoring the levels of urea and creatinine in the patient with
impaired kidney function represents a vast over-simplification of the uremic state.

Uremic syndrome
Water-soluble, hydrophobic, protein-bound, charged, and uncharged compound
Nitrogenous excretory
Compounds, urates and Hippocrates, products of nucleic acid metabolism, polyamines
Myoinositol, phenols, benzoates, and in doles
Urea and creatinine
Flow Chart No 2: Pathophysiology and Biochemistry of Uremia

The uremic syndrome and the disease state associated with advanced renal
impairment involve more than renal excretory failure. A host of metabolic and
endocrine functions normally undertaken by the kidneys are also impaired, and this
results in Anemia, malnutrition, and abnormal metabolism of carbohydrates, fats, and
proteins. Furthermore, plasma levels of many hormones, including PTH, insulin,
glucagon, sex hormones, and prolactin, change with renal failure as a result of
urinary retention, decreased degradation, or abnormal regulation. Finally, progressive
renal impairment is associated with worsening systemic inflammation. Elevated
levels of C-reactive protein are detected along with other acute-phase reactants,
while levels of so-called negative acute-phase reactants, such as albumin and fetuin,
decline with progressive renal impairment. Thus, renal impairment is important in
the malnutrition-inflammation-atherosclerosis/ calcification syndrome, which
contributes in turn to the acceleration of vascular disease and co morbidity associated
with advanced renal disease.



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Disturbance in metabolic and endocrinal functions
Anemia & Malnourishment
Abnormal metabolism
Carbohydrate, fats, proteins
Abnormal levels hormone
PTH, Insulin, Glucagon, Sex hormone, prolactin
Renal failure result
Urinary retention, decreased degradation,
Inflammation
Atherosclerosis/ calcification
Acceleration of vascular disease
Flow Chart No 3: Pathophysiology and Biochemistry of Uremia
In summary, the path physiology of the uremic syndrome can be
divided into manifestations in three spheres of dysfunction:
1) Those consequent to the accumulation of toxins normally undergoing renal
excretion, including products of protein metabolism.
2) Those consequent to the loss of other renal functions, such as fluid and
electrolyte homeostasis and hormone regulation.
3) Progressive systemic inflammation and its vascular and nutritional
consequences.
Chronic Kidney Disease:
Chronic kidney disease (CKD) encompasses a spectrum of different path
physiologic processes associated with abnormal kidney function, progressive decline
in glomerular filtration rate (GFR). Table1-1 provides a widely accepted
classification, based on recent guidelines of the National Kidney foundation (Kidney
Dialysis Outcomes Quality Initiative (KDOQI), in which stages of CKD are defined
according to the estimated GFR.



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The term chronic renal failure applies to the process of continuing significant
irreversible reduction in nephrons number, and typically corresponds to CKD stages
3-5. The path physiologic processes and adaptations associated with chronic renal
failure will be with the accumulation of toxins, fluid, and electrolytes normally
excreted by the kidneys results in the uremic syndrome. This syndrome leads to
death unless the toxins are removed by renal replacement therapy, using dialysis or
kidney transplantation.
TABLE 1-1 CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD)
Stage GFR, ml/ min per 1.73 m
2

0
>90

1 90
b

2
60-89

3
30-59

4
15-29

5
<15


with risk factors for CKD (see text)
b
with demonstrated kidney damage (e.g. persistent proteinuria, abnormal urine
sediment, abnormal blood and urine chemistry, abnormal imaging studies).
Note: GFR, Glomerular filtration rate.
Source: Modified from National Kidney Foundation. K/DOQI Clinical Practice
Guidelines for Chronic Kidney Disease: Evaluation, classification and stratification.
Am J Kidney Dis 39: suppl 1, 2002.
47


GFR Estimation:
Two equations commonly used to estimate GFR are shown in Table1-2 and
incorporate the measured plasma creatinine concentration, age, sex, and ethnic origin
reporting of estimated GFR, or e-GFR, using one of these equations.


47
NKF KDOQI GUIDELINES



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Table1-2
Recommended equations for Estimation of Glomerular Filtration Rate (GFR)
Using Serum Creatinine Concentration (Pc
r
), Age, Sex, Race and Body Weight
1. Equation from the Modification of Diet in Renal Disease study

Estimated GFR (mL/min per 1.73m
2
) = 1.86 X (Pc
r
)-
1.154
X (age)
-0.203

Multiply by 0.742 for women
Multiply by 1.21 for African Americans
2. Cockcroft-Gault equation
Estimated Creatinine Clearance (mL/min)
(140 Age X body weight, kg)
=-------------------------------------------------------------
72 X PC r (mg/dL)
Multiply by 0.85 for women

Equation is available in hand-held calculators and in tabular form.

Adapted from AS levey et al: Am J Kidney Dis 39(Suppl 1): S1, 2002, with
permission.

GFR with Age and Creatinine level:
The normal annual mean decline in GFR with age from the peak GFR
(~120mL/min per1.73m
2)
attained during the third decade of life is ~ 1 mL/ min per
year per1.73m
2,
reaching a mean value of 70mL/min per1.73m
2
at age 70. The mean
GFR is lower in women than in men. For example, a woman in her 80s with a
normal serum creatinine may have a GFR of just 50mL/ min per1.73m
2.
Thus, even a
mild elevation in serum creatinine concentration {e.g. 130 mol/L (1.5mg/dL)},
often signifies a substantial reduction in GFR in most individuals.
Mechanisms:-
Raised intra- glomerular pressure:
As nephrons scar and drop out, remaining nephrons undergo compensatory
adaptation, with blood flow per nephrons attempting to normalize GFR
(the Brenner Hypothesis).



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Glomerular capillary wall permeability is a feature of glomerular diseases.
Renal vasodilatation may be an initiating event, with the glomerular exposed
to a higher capillary pressure.
Glomerular damage:-
Intra glomerular pressure -> wall stress and endothelial injury.
Strain on mesangial cells -> matrix deposition mediated (in part) by
angiotensin II and cytokine release (TGF , PDGF).
Proteinuria: - May be due to an underlying glomerular lesion, or result from raised
intra glomerular pressure. Protein or factors bound to filtered albumin (such as fatty
acids, growth factors or metabolic end- products) may lead to:
Direct proximal tubular cell injury.
Local cytokine synthesis ( recruitment of interstitial inflammatory cells).
Pro-fibrotic factors interstitial scarring.
Trans- differentiation of tubular cells into fibroblasts.
Tubulointerstitial scarring: - The degree of tubulointerstitial damage correlates
better with long-term prognosis than glomerular damage. Proteinuria may itself be
harmful to the tubulointerstitial, but chronic ischemic damage is also important:
tissue oxygen tension is relatively low in the renal medulla, making tubules sensitive
to hypoxic injury. Chronic ischemia occurs with:
Damage to glomerular capillaries (glomerular sclerosis altered per tubular
perfusion).
RAS activation interregnal vasoconstriction.
Intra tubular capillary loss and increased diffusion distance between
capillaries and tubular cells, leads to vicious cycle of hypoxic.
Significance of Albuminuria, Proteinuria, Microalbumuria:
Measurement of albuminuria is also helpful for monitoring nephrons injury
and the response to therapy in many forms of CKD, especially chronic glomerular
diseases. While an accurate 24-h urine collection is the gold standard



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Modern literature Review
for measurement of albuminuria, the measurement of albumin-to- creatinine ratio in
a spot first- morning urine sample is often more practical to obtain and correlates
well, but not perfectly, with 24-h urine collections. Persistence in the urine of >17
mg of albumin per gram of creatinine in adult males and 25mg albumin per gram of
creatinine in adult females usually signifies chronic renal damage. Micro
albuminuria refers to the excretion of amounts of albumin too small to detect by
urinary dipstick or conventional measures of urine protein. It is a good screening test
for early detection of renal disease, in particular, and may be a marker for the
presence of micro vascular disease in general. If a patient has a large amount of
excreted albumin, there is no reason to perform an assay for micro albuminuria.
Progression of Diseases:
Stages 1 & 2 CKD:
Decreased GFR
Renal parenchymal disease
Poly cystic disease
Glomerular nephritis
Parnechymal and vascular diseases.
Well preserved GFR.
The usually are not associated with any symptoms arising from the decrement
in GFR. However, there may be symptoms from the underlying renal disease itself,
such as edema in patients with nephritic syndrome or signs of hypertension
secondary to the renal parenchymal disease in patients with polycystic kidney
disease, some forms of glomerular nephritis, and many other parenchymal and
vascular renal diseases, even with well-preserved GFR.
GFR progresses to stages 3 & 4:
Organs affected
Anemia
Associated
easy fatigability; decreasing appetite with progressive malnutrition


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Abnormality
calcium, phosphorus, mineral regulating hormone, Parathyroid hormone
sodium, potassium, water, and acid-base homeostasis
If the decline in GFR progresses to stages 3 & 4, clinical and laboratory
complications of CKD become more prominent. Virtually all organ systems are
affected, but the most evident complications include Anemia and associated easy
fatigability; decreasing appetite with progressive malnutrition, abnormalities in
calcium, phosphorus, and mineral regulating hormones, such as 1,25 (OH)
2
D
3

(calcitriol) and parathyroid bromine (PTH); and abnormalities in sodium, potassium,
water, and acid-base homeostasis.
Progresses to stage 5 CKD:
Disturbance
Nutritional status
Water and electrolyte homeostasis
If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually
experience a marked disturbance in their activities of daily living, well-being,
nutritional status, and water and electrolyte homeostasis, eventuating in the uremic
syndrome. This state will culminate in death unless renal replacement therapy
(dialysis or transplantation) is instituted.
CKD & Other disease (Anemia, Hypertension & diabetes)
Anemia of CKD
Erythropoietin (EPO) and the kidney:-
Red blood cell production is tightly regulated by a number of different
growth factors. EPO is essential for the terminal maturation of erythrocytes, and
differs from other growth factors in that it is produced by per tubular interstitial
fibroblasts in the outer renal medulla and deep cortex of the kidney rather than the
bone marrow. The kidney is ideally placed to regulate RBC production, as it is



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uniquely able to sense and control both O
2
tension and circulating volume (and
differentiate between the two):
Red cell mass is regulated by EPO.
Circulating volume is regulated by salt and water excretion.
The kidney maintains the haematocrit at 45% in normal conditions.
(maximizing tissue O
2
delivery)

Chronic kidney disease, renal scarring EPO synthesis, RBC production and
anemia this occurs in most form of advanced CKD (e GFR < 35 mL/min), with a few
exceptions:
Adult polycystic kidney disease.
Benign renal cysts.
Renal cell carcinoma.
In these instances, EPO may be overproduced.

Differential diagnosis of anemia in CKD patients:-
EPO deficiency is not the only cause of Hb in CKD
Patients with CKD are susceptible to all other causes of anemia, so these
should be actively sought in patients who appear disproportionately anemic or EPO
resistant:
Iron deficiency.
Blood loss (Gl tract, haemodialysis)
Foliate deficiency
B12 deficiency
Haemolysis
Myelodysplasia
Myeloma







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Modern literature Review
Hypertension
Hypertension is the second leading cause of end-stage renal disease
(ESRD). As an example, according to the United States Renal Data System (U. S.
Renal Data System, 2009), about 51 -63% of all patients with CKD are hypertensive.
This number grows to 90% in patients over 65years. In the corresponding general
population the incidence of hypertension is 11 13% and 50%, respectively.

Hypertension causes a nephrosclerotic glomerulopathy characterized by
i. Renal vasculopathy affecting pre glomerular arteries and arterioles, resulting
mainly from atherosclerosis, endothelial dysfunction, wall thickening and
fibrosis.
ii. Microvascular disease of the glomerular tuft capillaries.
iii. Diffuse glomerular sclerosis and, less often, focal and segmental glomerular
sclerosis (FSGS), involving damage to the filtration barrier constituents
(Podocytes, mesangial cells and basement membranes.
iv. Interstitial fibrosis (Rosario & Wesson, 2006). Overall renal blood flow
decreases as a consequence of arteriolar vasculopathy, vascular obstruction
and decrease vascular density. However, GFR initially stays relatively
constant. This is due to (i) increased glomerular capillary pressure resulting
from deficient or upwardly reset renal auto regulation; and (ii) damage to the
filtration barrier resulting in greater permeability. Subsequently, GFR
decreases as a consequence of a progressive loss of surface area, mesangial
hypertrophy and increasing glomerular and per tubular fibrosis.
Concomitantly, basement membrane alterations produce albuminuria and
protein hyper filtration.



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Modern literature Review


Renal vasculopathy

Micro vascular Disease

Filtration barrier damage

Interstitial fibrosis

GFR decreased

Alteration basement
Pre glomerular arteries and arterioles affected
Endothelial dysfunction
Wall thickening and fibrosis

Glomerular tuft capillaries


Podocytes mesangial cells and basement membrane

Arteriolar vasculopathy, vascular obstruction, depressed
vascular density

loss of surface area, mesangial hypertrophy, increasing
glomerular and per tubular fibrosis

proteinuria and alumunria
Flow Chart No. 4: Hypertension causes a nephrosclerotic glomerulopathy
characterized

Hypertension associated CKD progression is highly dependent on
(i) Renal blood flow auto regulation and renal hemodynamic.
(ii) Artificial maneuvers or genetically-determined factors that modify renal
function or renal tissue homeostasis, independently of their action on
blood pressure or renal hemodynamic.
(iii) Genetic susceptibility factors. Renal auto regulation endows the kidneys
with the capacity to maintain constant glomerular flow and pressure upon
changes in systemic and renal perfusion pressure. Auto regulation is
attained through vasoconstriction and vasodilatation of pre glomerular
(afferent) arteries and arterioles. In addition to the insulation of renal
function from the influence of fluctuations in systemic blood pressure,
one of the most important physiological functions of auto regulation is
believed to be the protection of renal tissues from mechanical overload
derived from high blood pressure.
48


48
Pharmacology & Therapeutics, Common path physiological mechanisms of chronic kidney disease:
therapeutic perspective.


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Diabetic nephropathy:-
The diabetic nephropathy is leading cause of ESRD in the
USA and Europe (Molitch et al., 2004). In fact, about 50% of ESRD patients (in
the USA) are diabetic (U.S.Renal Data System, 2009). It is important to consider that
hyperglycemia is primary initiator of diabetic nephropathy. In the absence of
elevated glycemic, nephropathy does not develop. However, diabetic nephropathy
holds a genetic component at two levels: first, the elevation of glycemic; and second,
at establishing a genetic back- ground where nephropathy can occur (in the presence
of hyperglycemia). Only 30% of patients with type 1, and 35 40% of patients with
type 2 diabetes develop diabetic nephropathy irrespective of glycemic control
(Diabetes Control & Complications, 1995). The clinical history of a typical patient
starts with symptoms of hyper filtration (elevated values of GFR) and occasional
microalbuminuria, which may last approximately 5 years. During the next 20
years, microalbuminuria turns into progressively higher proteinuria, whereas GFR
declines. Finally, the patient undergoes renal insufficiency with severe proteinuria,
which eventually evolves towards ESRD (Schena & Gesualdo, 2005).
Diabetes patients
Type1-30%
Type2-35-40%
Hyper filtration (elevated values of GFR) 5years



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Modern literature Review
Diagnosing CKD:-
Always assume a e GFR represents acute renal failure until proven
otherwise. If uncertain, repeat within 5 day and refer as necessary.


TABLE 10: Manifestations Attributable to Uraemic Toxins
Cardiovascular system
Atheromatosis
Arteriosclerosis
Cardiomyopathy
Decreased diastolic
compliance
Nervous system
Concentration disturbances
Cramps
Dementia
Depression
Fatigue
Headache
Seizures
Asterixis (flaps)
Motor weakness
Polyneuritis
Reduced sociability
Restless legs
Sleep disorders
Stupor, coma
Haematological system
Bleeding
Hypercoagulability
Immunological system
Inadequate antibody
formation
Stimulation of inflammation
Susceptibility of cancer
Susceptibility of infection

Endocrinology
Dyslipidaemia
Glucose tolerance
Growth retardation
Hyperparathyroidism
Mpotence, diminished libido
Bone disease
Adynamic bone disease
Amyloidosis
Osteitis fibrosa
Osteomalacia
Osteoporosis
Skin
Melanosis
Pruritus
Uraemia frost
Gastrointestinal system
Anorexia
Dyspepsia
Hiccups
Nausea, vomiting
Pancreatitis
Pulmonary system
Pleuritis
Sleep apnoea syndrome
Miscellaneous
Hypothermia
Thirst
Uraemic foetor
Weight loss